1. Field of Invention
The present invention relates to a technical field of compounds which are phosphodiesterase inhibitors, and more particularly to biphenyls PDE4D inhibitors without vomiting, which are adapted for treating depression and Alzheimer's disease, and improving cognitive ability.
2. Description of Related Arts
Phosphodiesterase 4 (PDE4) is mainly distributed in inflammatory cells (such as mast cells, macrophages, lymphocytes and epithelial cells) and neurons. PDE4 plays an important role in the central nervous system and immune system, and its specific inhibitors are regarded as new anti-inflammatory and central nervous system candidate drugs which act on the intracellular targets. PDE4 specifically catalyzes the hydrolysis of cAMP, and plays a key role in controlling the intracellular levels of cAMP. So PDE4 inhibition would lead to the accumulated concentration of intracellular cAMP, and then cause a variety of biological effects, such as anti-inflammation, anti-depression, enhancing memory, improving cognitive function and so on.
The first-generation PDE4 inhibitor such as rolipram has good antidepressant effect, but cannot be listed for its nausea and vomiting and other side effects from inhibiting PDE4. Compared with the first-generation PDE4 inhibitor, the second-generation PDE4 inhibitor has better therapeutic effect. However, the PDE4 inhibitor without vomiting has not yet been listed. Therefore, there is an urgent need to develop a new PDE4 inhibitor with reducing or even avoiding vomiting, and meanwhile with anti-depressing and improving the cognitive function.
PDE4 is encoded by four genes (A-D) that give rise to four isoforms. PDE4 isoforms (A-D) have multiple transcription units and promoters, and encoded over 20 different variants of this enzyme. By the researching results of Hanting zhang on PDE4D gene null mice, it is shown that PDE4D is closely related to depression and cognitive function, meanwhile related to vomiting. And many literatures confirmed this conjecture.
All experimental results show that PDE4 inhibitors may be competitive inhibitors of cAMP (Houslay, et al. 2005, DDT, 10, 1503-2119), which can also explain why the cure rate of the PDE4 inhibitors are low.